2005 Grant - Wolfe

Inhibitors of Amyloid Production Selective for APP Vis-à-Vis Notch

2005 Investigator-Initiated Research Grant

Beta-amyloid is a tiny protein fragment that may be a key toxic factor in Alzheimer's disease. It is clipped from the larger amyloid precursor protein (APP) in a two-stage process. The second of these cuts is made by a cluster of proteins called gamma-secretase. One strategy under investigation as an Alzheimer treatment is the development of a gamma-secretase–inhibiting compound.

A potential problem with this strategy is that gamma-secretase also clips a protein called Notch, and this clipping is an important step in Notch's role in nerve cell development. Therefore, scientists are searching for compounds that selectively block the production of beta-amyloid but do not block the processing of Notch.

Michael S. Wolfe, Ph.D., and colleagues have screened approximately 60,000 compounds to identify ones that meet those criteria. They are now examining the most promising of these compounds to determine (1) what molecular event is affected by each compound and how does that event mediate the activity of gamma-secretase, (2) whether any of the compounds can be modified to improve the beta-amyloid lowering function and (3) what specific molecules are targeted by each of the compounds.

The outcome of this work may identify the most promising targets for drug development and suggest compounds for further investigation of their potential therapeutic value.